The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2(V617F) and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013. Coupled with increased knowledge of disease pathogenesis and refined diagnostic criteria and prognostic scoring systems, a more nuanced appreciation has emerged of the burden of MPN in the United States, including the prevalence, symptom burden, and impact on quality of life. Biological advances in MPN have translated into the rapid development of novel therapeutics, culminating in the approval of the first treatment for MF, the JAK1/JAK2 inhibitor ruxolitinib. However, certain practical aspects of care, such as those regarding diagnosis, prevention of vascular events, choice of cytoreductive agent, and planning for therapies, present challenges for hematologists/oncologists, and are discussed in this article.
Background: ABL001 is a potent, specific BCR-ABL inhibitor in development for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. ABL001 binds a pocket on the BCR-ABL kinase domain normally occupied by the myristoylated N terminus of ABL1, which serves an autoregulatory function subsequently lost upon fusion with BCR. ABL001 functionally mimics this autoregulatory role and restores negative regulation of kinase activity. In preclinical studies, ABL001 selectively inhibits the growth of BCR-ABL-positive cells, with activity noted against clinically observed TKI resistance mutations. ABL001 exhibits potent antitumor activity in KCL-22 xenografts, with evidence of complete tumor regression correlating with pSTAT5 inhibition. Animals receiving ABL001 and nilotinib in combination achieved sustained tumor regression without emergence of resistant disease even after treatment discontinuation. Methods: Patients with CML in chronic or accelerated phase with failure of ≥ 2 prior TKIs due to resistance or intolerance were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CABL001X2101). Escalating doses of single-agent ABL001 were administered orally on a continuous twice daily (BID) dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of ABL001 administered as a single agent, orally, BID. Secondary objectives included safety, preliminary anti-CML activity, and pharmacokinetics of ABL001. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Efficacy analysis was based on hematologic, cytogenetic, and molecular assessments. Results: At data cutoff, 35 patients had been treated at the following BID doses: 10 mg (n = 1), 20 mg (n = 5), 40 mg (n = 12), 80 mg (n = 11), 150 mg (n = 6), and MTD has not yet been reached. Median age was 56 years (range, 23-74 years). Most patients (97%) had baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated; 20 (57%) had received ≥ 3 prior TKIs. In 30 patients, treatment is ongoing at doses 20-150 mg BID, with median duration of exposure of 20.9 weeks (range, 0-49.7 weeks), and 5 patients discontinued (disease progression [n = 1], AEs [n = 3], stem cell transplant [n = 1]). Preliminary data suggests ABL001 pharmacokinetics is dose-proportional with minimal accumulation across dose and time. There were 3 DLTs: 1 grade 3 lipase elevation and 1 grade 2 arthralgia at 40 mg BID and 1 acute coronary syndrome at 150 mg BID. In addition, 3 cases of grade 2 acute pancreatitis occurred in cycle 5 at doses ≥ 80 mg BID. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were anemia (9%), thrombocytopenia (6%), neutropenia (6%), and lipase increase (6%). No deaths have occurred on study. 20 patients (10-80 mg) on therapy for ≥ 3 months had hematologic, cytogenetic, and molecular assessments. 17 patients were resistant to and 3 were intolerant of prior TKIs. Evidence of single agent activity was noted at doses ≥ 10 mg BID. All patients in complete hematologic (CHR) or complete cytogenetic (CCyR) response or with BCR-ABL ≤ 0.1 % IS at baseline have maintained responses. All 5 patients in hematologic relapse achieved CHR within 3 months. 9 of 11 TKI-resistant patients in cytogenetic relapse (> 65% Ph+ metaphases at baseline) achieved a major cytogenetic response by 3 months, including 6 who achieved CCyR. Of 17 TKI-resistant patients with baseline BCR-ABL > 0.1 % IS, 11 achieved a ≥ 1-log reduction in BCR-ABL % IS and 5 achieved major molecular response by 5 months. Clinical activity was seen across TKI-resistant mutations, including Y253H and V299L. Only 1 patient in accelerated phase has relapsed on study, with relapse due to a mutation in the myristoyl pocket. Conclusion: ABL001 exhibits rapid dose-dependent antitumor activity and appears well tolerated to date in a heavily pretreated subgroup of patients with CML, providing proof of principle of the effectiveness of allosteric inhibition of the BCR-ABL kinase in the treatment of CML. The phase 1 study is ongoing in dose escalation. Disclosures Ottmann: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees. DeAngelo:Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Ariad: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Agios: Consultancy; Novartis: Consultancy. Goh:Roche: Honoraria; Janssen: Honoraria, Research Funding; Gilead Sciences: Honoraria; Sanofi: Honoraria; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria. Heinrich:Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Blueprint Pharmaceuticals: Consultancy; Ariad: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; MolecularMD: Consultancy, Equity Ownership, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Hughes:ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mahon:ARIAD: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria. Mauro:Novartis Pharmaceutical Corporation: Consultancy, Research Funding; Ariad: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Minami:Novartis: Honoraria, Other: Member of IDMC , Research Funding. Rea:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria. Steegmann:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Chatterjee:Novartis Pharmaceuticals: Employment. Iyer:Novartis Pharmaceuticals: Employment, Equity Ownership. Martinez:Novartis Institute for Biomedical Research: Employment. Vanasse:Novartis Pharmaceuticals: Employment, Equity Ownership. Dong-Wook:ll-Yang: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau.
TPS8574 Background: cCRT improves survival vs RT alone and is a global standard of care in patients (pts) with stage III NSCLC, but survival remains poor for these pts. Combining PD-1/PD-L1-targeting immunotherapies and cCRT may lead to synergistic activity and improved outcomes. Tislelizumab (anti–PD-1) demonstrated clinical activity and tolerability in solid tumors, including NSCLC. This phase III, randomized, double-blind, placebo-controlled study (RATIONALE 001) will evaluate efficacy and safety of tislelizumab + cCRT. Methods: Pts (N ≈ 840) will be randomized 1:1:1 in a 3-arm study design to evaluate whether the timing of giving tislelizumab earlier upfront with cCRT in addition to as consolidation (Arm 1) or giving tislelizumab as consolidation only (Arm 2) will improve outcomes vs cCRT alone (Arm 3; Table). RT will be given in 2 Gy fractions to a target dose of 60 Gy (30 fractions). Chemotherapy will be investigator’s choice of cisplatin + etoposide or carboplatin + paclitaxel. A safety analysis specific to the cisplatin + etoposide component of the cCRT + tislelizumab combination is planned. All sites must pass a radiation quality assurance review process. The primary endpoint is PFS. Secondary endpoints include ORR, OS, OS at 24 months, and safety. As an exploratory endpoint, blood and tumor biomarkers will be assessed for correlations with clinical benefit. With a one-sided α of 1.25%, a total of 580 PFS events are required to allow ≈ 90% power to detect a HR for progression or death of 0.7 for either pairwise comparison (Arm 1 vs Arm 3 or Arm 2 vs Arm 3). Key eligibility criteria are locally advanced, unresectable, stage III NSCLC; FDG-PET and brain imaging confirmation of stage III status; no prior treatment; and ECOG PS ≤ 1. PD-L1 expression assessment is not required prior to randomization. EudraCT number 2018-001132-22. Clinical trial information: NCT03745222. [Table: see text]
Oral corticosteroids are first-line therapy for allergic bronchopulmonary aspergillosis (ABPA), however, itraconazole has been recognized as an adjunctive treatment. This paper describes the prolonged use of itraconazole in an asthmatic patient with a diagnosis of ABPA. This case report features a patient who showed benefit with a longer duration of itraconazole therapy without demonstrating adverse events related to treatment over nearly eight years. Prolonged treatment with itraconazole may serve as a corticosteroid sparing option for ABPA patients.
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